CN115624656B

CN115624656B - Drug coating balloon catheter and preparation method thereof

Info

Publication number: CN115624656B
Application number: CN202211545424.7A
Authority: CN
Inventors: 张鹏; 吕纬岩; 王健; 梁友; 邵伟
Original assignee: Beijing Jiushi Shenkang Medical Technology Co ltd
Current assignee: Beijing Jiushi Shenkang Medical Technology Co ltd
Priority date: 2022-12-05
Filing date: 2022-12-05
Publication date: 2023-03-21
Anticipated expiration: 2042-12-05
Also published as: CN115624656A

Abstract

The invention relates to a preparation method of a drug-coated balloon catheter, which comprises a balloon body, a distal rod and a proximal rod which are sequentially connected, and the preparation method comprises the following steps: mixing rapamycin and grinding powder to generate a grinding mixture, and sequentially carrying out vortex grinding treatment and first water bath ultrasonic treatment; filtering the ground mixture subjected to the first water bath ultrasonic treatment for multiple times to obtain medicine particles; mixing the drug particles with a poor solvent and carrying out second water bath ultrasonic treatment to obtain a bottom layer mixed solution; arranging the balloon body in the bottom layer mixed liquid to carry out bottom layer coating treatment; mixing the medicine particles with a benign solvent, carrying out first water bath treatment until the medicine particles are dissolved, and then adding a poor solvent to carry out second water bath treatment to obtain a surface layer mixed solution; arranging the balloon body subjected to bottom layer coating treatment in a surface layer mixed solution for surface layer coating treatment; and (4) carrying out surface layer shading drying treatment on the balloon catheter subjected to surface layer coating treatment.

Description

Drug coating balloon catheter and preparation method thereof

Technical Field

The invention relates to the technical field of medical instruments, in particular to a drug coating balloon catheter and a preparation method thereof.

Background

Intracranial atherosclerosis is the most common vascular disease of patients with cardiovascular and cerebrovascular diseases, and is one of the most common causes of stroke. Intracranial atherosclerosis can result in thickening and hardening of the cerebral artery walls, narrowing of the lumen, and even occlusion, resulting in reduced or interrupted blood flow in the artery. Statistics show that intracranial atherosclerosis accounts for about 46.6% of ischemic stroke vascular diseases, while patients with intracranial atherosclerosis have heavier symptoms and longer hospitalization time, and the recurrence rate of stroke is increased along with the increase of the degree of cerebrovascular stenosis.

At present, the main treatment methods for intracranial atherosclerotic stenosis include drug treatment, pure balloon dilatation and intravascular stent. Clinically, the treatment of cerebrovascular ICAS (all called intracranial atherosclerotic stenosis) is mainly by long-term oral antiplatelet drugs and controlling risk factors such as hyperlipidemia, hypertension, diabetes, smoking, etc. Although this has some effect in reducing the incidence of stroke in patients with cerebrovascular ICAS, the actual clinical outcome is not entirely satisfactory, especially in patients with unstable plaques and hemodynamic cerebral ischemic events. For ICAS patients with high intracranial main artery stenosis degree (high stenosis degree means a stenosis rate of 70-99%), even if the patients can receive proper drugs for treatment, the recurrence rate of stroke is still high, and the drug side effects such as liver and kidney function damage and the like caused by long-term drug treatment are not ignored. As for the treatment of intracranial main arterial stenosis by pure balloon dilatation, restenosis and other problems are easy to exist. The vascular stent belongs to intravascular implants, and patients implanted with the vascular stent need to take double-resistant medicaments for a long time, so that the problems of inflammation, thrombosis, restenosis and the like exist.

In recent years, drug-coated balloon catheters (DCBs) have become widely used in the coronary and peripheral interventional fields in europe as a new interventional treatment technique. On one hand, the drug-coated balloon catheter is used as an interventional instrument, so that the risks of endothelialization disorder, late thrombosis, inflammation and the like caused by continuous contact of drugs with the inner wall of a blood vessel in the blood vessel by using the intravascular stent as a permanent implant are avoided. On the other hand, drug-coated balloon catheters also provide a short-lived and controlled drug to inhibit endothelial hyperplasia in blood vessels.

At present, the domestic market also has the investment of drug-coated balloon catheters, and a plurality of the drug-coated balloon catheters are already put into clinical use or are about to be put into clinical use. The existing drug coating balloon catheter needs to adopt matrix, polymer and other components to take paclitaxel, paclitaxel derivatives, rapamycin and rapamycin derivatives as active drug coatings. Drug-coated balloon catheters containing a matrix and a polymer component present potential risks. In addition, according to related studies, the drug-coated balloon catheters currently used in angioplasty (mainly peripheral and coronary), all of which are paclitaxel, have drug coatings. However, paclitaxel has cytotoxicity, a narrow safe dose range, and a weaker effect in inhibiting restenosis than rapamycin, and these disadvantages have been confirmed in coronary drug stents. While rapamycin is used as a drug coating, the poor lipophilicity of rapamycin results in slow absorption at the target lesion site.

Disclosure of Invention

The invention provides a drug-coated balloon catheter and a preparation method thereof, which aim to solve the technical problems of slow absorption of a target lesion part and low drug transfer rate and utilization rate caused by poor lipophilicity of the existing drug-coated balloon catheter adopting rapamycin as a drug coating.

The invention discloses a preparation method of a drug-coated balloon catheter, wherein the drug-coated balloon catheter comprises a balloon body, a distal rod and a proximal rod which are sequentially connected, and the preparation method of the drug-coated balloon catheter comprises the following steps: mixing rapamycin and/or rapamycin derivatives with grinding powder to generate a grinding mixture, and sequentially carrying out vortex grinding treatment and first water bath ultrasonic treatment; filtering the ground mixture subjected to the first water bath ultrasonic treatment for multiple times to obtain rapamycin and/or rapamycin derivative drug particles with the particle size ranging from 0.01um to 20um; mixing the medicine particles with a poor solvent and carrying out secondary water bath ultrasonic treatment to obtain a bottom layer mixed solution; arranging the balloon body in the bottom layer mixed liquid to carry out at least one bottom layer coating treatment; mixing the medicine particles with a benign solvent, carrying out first water bath treatment until the medicine particles are dissolved, and then adding a poor solvent to carry out second water bath treatment to obtain a surface layer mixed solution; arranging the balloon body subjected to bottom layer coating treatment in the surface layer mixed solution for at least one time of surface layer coating treatment; and (3) carrying out surface layer shading drying treatment on the balloon catheter subjected to surface layer coating treatment.

Further, rapamycin and/or rapamycin derivatives and the grinding medicinal powder are mixed according to the proportion of 1; and (3) carrying out vortex grinding treatment and first water bath ultrasonic treatment on the grinding mixture mixed with the n-heptane in sequence.

Further, the ground mixture after the first water bath ultrasonic treatment is filtered for multiple times to obtain drug particles, and the drug particles are subjected to vacuum drying treatment.

Further, the vortex grinding process comprises: and carrying out vortex grinding on the grinding mixture mixed with the n-heptane at 2500r/min for 3-4 h.

Further, the first water bath ultrasonic treatment comprises the following steps: carrying out water bath treatment on the grinding mixture after the vortex grinding treatment, wherein the temperature value range of the water bath is 10-40 ℃; and meanwhile, carrying out ultrasonic treatment on the ground mixture subjected to the water bath, wherein the frequency range of the ultrasonic treatment is 10-80 khz, and the treatment time is 2-6 min.

Further, the vacuum drying treatment comprises the following steps: and (3) arranging the medicine particles obtained by multiple times of filtration in a vacuum environment, wherein the temperature of the vacuum environment ranges from 20 ℃ to 80 ℃, and the treatment time is 0.1h to 12h.

Further, mixing the drug particles with a poor solvent according to a first volume ratio to generate a bottom layer mixture, wherein the value range of the first volume ratio is 0.00001-0.01; performing secondary water bath ultrasonic treatment on the bottom layer mixture to obtain a bottom layer mixed solution; the second water bath ultrasonic treatment comprises the following steps: carrying out water bath treatment on the bottom layer mixture, wherein the temperature range of the water bath is 20-40 ℃; and meanwhile, carrying out ultrasonic treatment on the bottom layer mixture subjected to the water bath, wherein the frequency range of the ultrasonic treatment is 10-80 khz, and the treatment time is 1-20 min.

Further, the primer coating process includes: and arranging the balloon body in the bottom layer mixed liquid subjected to the second water bath ultrasonic treatment for ultrasonic treatment, wherein the frequency range of the ultrasonic treatment is 10-80 khz, and the treatment time is 1-20 min.

Further, the balloon body which is subjected to bottom layer coating treatment is not subjected to bottom layer shading drying treatment; or, carrying out bottom layer shading drying treatment on the balloon body subjected to bottom layer coating treatment, wherein the treatment time is 0.1-24 h.

Further, mixing the drug particles with a benign solvent according to a second volume ratio to generate a surface layer mixture, wherein the value range of the second volume ratio is 0.001-2; carrying out water bath heating treatment on the surface layer mixture until the medicine particles in the surface layer mixture are completely dissolved to obtain a primary surface layer mixed solution, wherein the value range of the water bath heating treatment temperature is 20-40 ℃; and mixing the poor solvent and the preliminary surface layer mixed liquid according to a third volume ratio to obtain the surface layer mixed liquid, wherein the value range of the third volume ratio is 0.1-20.

Further, the surface coating treatment comprises; and (3) arranging the balloon body subjected to bottom coating treatment in the surface layer mixed solution for soaking for 0.1-60 min.

Further, the balloon body subjected to surface coating treatment is subjected to surface layer light-shielding drying treatment, and the treatment time is 0.1-24 hours.

The invention also discloses a drug coating balloon catheter which is prepared by the preparation method of any one of the drug balloon catheters, and the drug balloon catheter comprises at least one bottom drug coating and at least one surface drug coating.

The drug coating balloon catheter and the preparation method thereof provided by the invention can realize the following technical effects:

1. the bottom layer drug coating and the surface layer drug coating of the drug-coated balloon catheter prepared by the method are both composed of rapamycin drug particles with the particle size ranging from 0.01um to 20um, and the bottom layer drug coating and the surface layer drug coating formed by the rapamycin drug particles can improve the drug release rate and reduce the loss of the balloon body in the conveying process. .

2. The drug-coated balloon catheter prepared by the method adopts the rapamycin drug particles with the particle size ranging from 0.01um to 20um to form the uniform and compact bottom drug coating and the surface drug coating, and also overcomes the defect of poor lipophilicity of the rapamycin, so that the absorption speed of a target lesion part is increased, and the transfer rate and the utilization rate of the drug are increased.

3. According to the drug-coated balloon catheter prepared by the method, the bottom drug coating and the surface drug coating are pure drug coatings coated by rapamycin, so that potential risks are reduced.

The foregoing general description and the following description are exemplary and explanatory only and are not restrictive of the invention.

Drawings

One or more embodiments are illustrated in the accompanying drawings, which correspond to the accompanying drawings and which are not to be construed as limiting the embodiments, in which elements having the same reference numeral designations are considered to be similar elements, and in which:

FIG. 1 is a schematic view of one embodiment of a drug-coated balloon catheter of the present invention;

fig. 2 is an enlarged view of a portion a of fig. 1.

Reference numerals:

1. a balloon body; 2. a distal stem; 3. a proximal shaft; 4. a bottom drug coating; 5. and (5) coating the surface layer with a medicament.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The drug-coated balloon catheter and the method for manufacturing the same according to the embodiment of the present invention will be described in detail below.

In the invention, the drug of the drug-coated balloon catheter can adopt rapamycin or rapamycin derivatives, and also can adopt rapamycin and rapamycin derivatives. Compared with taxol which is taken as a medicine coating, the rapamycin and rapamycin derivatives which are taken as the medicine coating have lower cytotoxicity and wider safe dosage range. Poor solvents for rapamycin include n-heptane, n-hexane, or chemical agents having the same or similar chemical properties as the aforementioned agents. Benign solvents of rapamycin include ethyl acetate, acetonitrile, tetrahydrofuran, methanol, or chemicals that are the same or similar in chemical nature to the aforementioned agents. The powder of the grinding powder comprises zirconium silicate, zirconium oxide, silicon oxide, aluminum oxide, or the same or similar substances. In the following description, rapamycin and n-heptane are used as poor solvents and ethyl acetate is used as benign solvent.

The invention provides a preparation method of a drug-coated balloon catheter, wherein the drug-coated balloon catheter comprises a balloon body 1, a distal rod 2 and a proximal rod 3 which are sequentially connected, and the preparation method of the drug-coated balloon catheter provided by the invention comprises the following steps:

A. preparation of pharmaceutical granules of rapamycin:

step a1, adding 1 part by weight of rapamycin and 10 parts by weight of zirconia into a test tube, and mixing to generate a grinding mixture, wherein the mixing ratio of rapamycin to zirconia is 1. The rapamycin is ground by the zirconia, so that the particle size of drug particles of the rapamycin can be smaller. For example, a test tube is charged with 1g of rapamycin and 10g of zirconia.

And step a2, continuously adding 1-50 ml of n-heptane into the test tube. Step a2 is an optional step, and by utilizing the property that n-heptane is incompatible with rapamycin and zirconia, the n-heptane is added into the grinding mixture to provide a liquid grinding environment for the grinding mixture, so that grinding can be more sufficient, and floating particles are prevented from being generated during grinding.

And a3, placing the test tube into a vortex mixing instrument for vortex grinding treatment. The rotational speed of the vortex mixer was set at 2500r/min, and the milled mixture in the test tube was also subjected to vortex milling at the same rotational speed. The duration of the vortex grinding treatment is 3-4 h, so that the rapamycin can be fully ground.

Preferably, the duration of the vortex grinding treatment is 3.5 hours, so that the rapamycin can be fully ground, and the grinding time can be saved.

And a4, taking the test tube out of the vortex mixing instrument, and putting the test tube into an ultrasonic cleaning machine for carrying out first water bath ultrasonic treatment. In the ultrasonic cleaning machine, the grinding mixture in the test tube is heated in a water bath, and the temperature of the water bath ranges from 10 ℃ to 40 ℃. Meanwhile, ultrasonic waves are also adopted to carry out ultrasonic treatment on the grinding mixture in the test tube, and the frequency range of the ultrasonic waves is 10-80 khz. The time of the first water bath ultrasonic treatment is 2min to 6min. The arrangement can generate high-frequency oscillation of the rapamycin in the n-heptane, and the rapamycin is uniformly distributed in the n-heptane, so that the subsequent filtering and drying treatment is convenient.

Preferably, the time length of the first water bath ultrasonic treatment is 3min. The rapamycin can be distributed in n-heptane more uniformly, and the grinding time can be saved.

And a5, filtering the ground mixture subjected to the first water bath ultrasonic treatment for multiple times by using a filter to obtain mixed liquid of rapamycin drug particles and n-heptane, and containing the mixed liquid by using a test tube.

And a6, pouring the mixed liquid of the rapamycin drug particles and n-heptane in the test tube into an evaporation dish, and putting the evaporation dish into a vacuum drying oven for vacuum drying treatment. And (3) drying the evaporating dish in a vacuum environment, so that the rapamycin drug particles and the n-heptane can be separated and dried conveniently. The temperature of the vacuum environment in the vacuum drying oven ranges from 20 ℃ to 80 ℃. The duration of the vacuum drying treatment is 0.1 to 12 hours. Such temperatures do not impair the pharmaceutical properties of rapamycin. Until n-heptane in the evaporation dish is completely evaporated, the residual medicine particles of rapamycin are the medicine particles of rapamycin, the value range of the particle size of the medicine particles of rapamycin is 0.01um to 20um, the medicine particles of rapamycin belong to nano-scale microparticles, the adhesion force is stronger, and the falling and loss of the medicine particles in the transportation process of the balloon body 1 are reduced.

B. Preparing a bottom layer mixed solution:

and b1, putting the rapamycin drug particles and n-heptane into a test tube according to a first volume ratio, and mixing to generate a bottom layer mixture, wherein the value range of the first volume ratio is 0.00001-0.01.

And b2, putting the test tube filled with the bottom layer mixture into an ultrasonic cleaning machine for second water bath ultrasonic treatment. In an ultrasonic cleaning machine, a water bath mode is adopted to heat the bottom layer mixture in the test tube, and the temperature range of the water bath is 20-40 ℃. Meanwhile, ultrasonic waves are also adopted to carry out ultrasonic treatment on the bottom layer mixture in the test tube, and the frequency range of the ultrasonic waves is 10-80 khz. The time length of the second water bath ultrasonic treatment is 1 min-20 min. And finally obtaining a bottom layer mixed solution after the bottom layer mixture is subjected to second water bath ultrasonic treatment. The arrangement can generate high-frequency oscillation of the rapamycin in the n-heptane, and the rapamycin is uniformly distributed in the n-heptane, so that the subsequent bottom coating is convenient.

Preferably, the time length of the second water bath ultrasonic treatment is 10min. The rapamycin can be distributed in n-heptane more uniformly, and the grinding time can be saved.

C. Bottom coating of the drug-coated balloon catheter:

and step c1, taking the test tube filled with the bottom layer mixed solution out of the ultrasonic cleaning machine.

And c2, inflating the balloon catheter, and inserting the balloon body 1 of the balloon catheter into the bottom layer mixed liquid in the test tube.

And c3, putting the test tube into an ultrasonic cleaning machine for ultrasonic treatment, wherein the frequency range of ultrasonic waves is 10-80 khz, and the time of ultrasonic treatment is 1-20 min. Ultrasonic treatment is carried out while the drug particles of rapamycin are precipitated on the surface of the balloon body 1, so that the drug particles of rapamycin can be more uniformly precipitated on the balloon body 1 to form a bottom drug coating 4. The coating of the bottom drug coating 4 on the balloon body 1 enables the surface drug coating 5 to be more stably fixed on the balloon body 1.

And c4, taking the balloon catheter out of the bottom layer mixed liquid.

And c5, carrying out bottom layer light-shading treatment on the balloon catheter taken out of the bottom layer mixed solution, wherein the time for drying the bottom layer in the light-shading manner is 0.1-24 hours. The bottom layer light-shielding drying treatment refers to a light-shielding drying treatment performed after the bottom layer coating is performed on the balloon body 1. The bottom drug coating 4 of the balloon body 1 is treated in a light-shielding drying treatment mode, so that the influence of light on the bottom drug coating 4 formed by drug particles can be avoided. This step is an optional step.

D. Step C is performed at least once.

E. Preparing a surface layer mixed solution:

and e1, putting the rapamycin drug particles and ethyl acetate into a test tube according to a second volume ratio to mix to generate a surface layer mixture, wherein the value range of the second volume ratio is 0.001-2.

And e2, putting the test tube filled with the surface layer mixture into a water bath kettle for water bath heating treatment until the rapamycin medicine particles in the surface layer mixture are completely dissolved, thereby obtaining a primary surface layer mixed solution. The temperature range of the water bath heating treatment is 20-40 ℃.

And e3, adding n-heptane into the test tube filled with the preliminary surface layer mixed solution, wherein the volume ratio of the n-heptane to the preliminary surface layer mixed solution is a third volume ratio, and the value range of the third volume ratio is 0.1-20. And dispersing and mixing n-heptane in the primary surface mixed liquid by utilizing the continuous water bath heating treatment of the water bath to form surface mixed liquid. And adding n-heptane into the primary surface layer mixed solution, wherein the n-heptane is used for reducing the solubility of rapamycin drug particles and is more beneficial to forming a surface layer drug coating 5.

F. Coating the surface layer of the drug-coated balloon catheter:

f1, inserting the balloon body 1 subjected to bottom coating treatment into the surface layer mixed solution in the test tube, and soaking for 0.1-60 min. This facilitates further precipitation of the drug particles of rapamycin on the bottom drug coating 4 of the balloon body 1 and formation of the top drug coating 5.

And f2, taking the balloon catheter out of the test tube, and then carrying out surface layer light-shading drying treatment on the balloon catheter, wherein the time duration of the surface layer light-shading drying treatment is 0.1-24 h. The surface layer light-shielding drying treatment is performed after the surface layer of the balloon body 1 is coated. The surface drug coating 5 of the balloon body 1 is treated in a light-shielding drying treatment mode, so that the influence of light on the surface drug coating 5 formed by drug particles can be avoided.

G. Step F is performed at least once.

The balloon catheter with the drug coating can be obtained through the treatment of the steps.

The drug coating balloon catheter prepared by the process is not only suitable for intracranial tortuous intracranial arterial vessels, but also suitable for heart and peripheral arterial vessels.

The bottom layer drug coating and the surface layer drug coating of the drug-coated balloon catheter prepared by the method both consist of rapamycin drug particles with the particle size ranging from 0.01um to 20um, the bottom layer drug coating and the surface layer drug coating formed by the rapamycin drug particles can improve the drug release rate, and can reduce the loss of the balloon body in the transportation process.

Meanwhile, the drug-coated balloon catheter prepared by the method adopts the rapamycin drug particles with the particle size ranging from 0.01um to 20um to form a uniform and compact bottom drug coating and a surface drug coating, and the defect of poor lipophilicity of the rapamycin is overcome, so that the absorption speed of a target lesion part is increased, and the drug transfer rate and the utilization rate are increased.

According to the drug-coated balloon catheter prepared by the method, the bottom drug coating and the surface drug coating are pure drug coatings coated by rapamycin, so that potential risks are reduced.

Preferably, in order to make the coating more uniform, in the embodiment of the present invention, ultrasonic coating may be used for the primer coating and the top coating. The specific manner of ultrasonic coating may refer to the prior art, and is not described herein in detail.

The drug-coated balloon catheter provided by the invention can be prepared by the preparation method of the drug-coated balloon catheter, and can also be prepared by other existing methods, but whatever the preparation method is adopted, the structure of the prepared drug-coated balloon catheter needs to meet the following requirements:

as shown in fig. 1 and fig. 2, the invention further provides a drug-coated balloon catheter, which is prepared by the preparation method of the drug-coated balloon catheter according to any one of the alternative embodiments. The drug balloon catheter comprises at least one bottom drug coating 4 and at least one surface drug coating 5.

Preferably, when the number of the bottom drug coatings 4 and the number of the top drug coatings 5 are both multiple, the bottom drug coatings 4 and the top drug coatings 5 are sequentially and alternately arranged on the outer surface of the balloon body 1. The mode that the bottom layer drug coating 4 and the surface layer drug coating 5 are alternately arranged can effectively control the release speed of the drug coatings and lead the release speed of the drug particles to be regular. The multilayer herein is at least two layers, for example, two layers, or three layers, or four layers, etc. may be employed.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims

1. A preparation method of a drug-coated balloon catheter, which comprises a balloon body, a far-end rod and a near-end rod which are sequentially connected, is characterized by comprising the following steps:

mixing rapamycin and/or rapamycin derivatives with grinding powder to generate a grinding mixture, and sequentially carrying out vortex grinding treatment and first water bath ultrasonic treatment;

filtering the ground mixture subjected to the first water bath ultrasonic treatment for multiple times to obtain rapamycin and/or rapamycin derivative drug particles with the particle size ranging from 0.01um to 20um;

mixing drug particles of rapamycin and/or rapamycin derivatives with a poor solvent according to a first volume ratio to generate a bottom layer mixture, wherein the value range of the first volume ratio is 0.00001-0.01;

carrying out secondary water bath ultrasonic treatment on the bottom layer mixture to obtain a bottom layer mixed solution;

arranging the balloon body in the bottom layer mixed liquid to carry out at least one bottom layer coating treatment;

the bottom layer coating treatment comprises the steps of not carrying out bottom layer shading drying treatment on the balloon body subjected to the bottom layer coating treatment, or carrying out bottom layer shading drying treatment on the balloon body subjected to the bottom layer coating treatment;

mixing the drug particles of the rapamycin and/or the rapamycin derivative with a benign solvent according to a second volume ratio to generate a surface layer mixture, wherein the value range of the second volume ratio is 0.001-2;

carrying out water bath heating treatment on the surface layer mixture until the rapamycin and/or rapamycin derivative drug particles in the surface layer mixture are completely dissolved to obtain a primary surface layer mixed solution, wherein the value range of the water bath heating treatment temperature is 20-40 ℃;

mixing the poor solvent and the preliminary surface layer mixed solution according to a third volume ratio to obtain a surface layer mixed solution, wherein the value range of the third volume ratio is 0.1-20;

arranging the balloon body subjected to bottom layer coating treatment in a surface layer mixed solution for at least one time of surface layer coating treatment;

and (4) carrying out surface layer shading drying treatment on the balloon catheter subjected to surface layer coating treatment.

2. The method for preparing a drug-coated balloon catheter according to claim 1,

mixing rapamycin and/or rapamycin derivatives with the grinding powder according to the proportion of 1;

the milled mixture mixed with n-heptane was subjected to vortex milling treatment and first water bath ultrasonic treatment in this order.

3. The method for preparing a drug-coated balloon catheter according to claim 2,

and carrying out vacuum drying treatment on the drug particles of the rapamycin and/or the rapamycin derivative obtained by filtering the ground mixture subjected to the first water bath ultrasonic treatment for multiple times.

4. The method for preparing a drug-coated balloon catheter according to claim 3, wherein the vortex grinding treatment comprises:

the milled mixture mixed with n-heptane was subjected to vortex milling at 2500r/min for a treatment time of 3-4 h.

5. The method for preparing a drug-coated balloon catheter according to claim 4, wherein the first water bath ultrasonic treatment comprises:

carrying out water bath treatment on the grinding mixture after the vortex grinding treatment, wherein the temperature value range of the water bath is 10-40 ℃; and meanwhile, carrying out ultrasonic treatment on the ground mixture subjected to the water bath, wherein the frequency range of the ultrasonic treatment is 10-80 khz, and the treatment time is 2-6 min.

6. The method for preparing a drug-coated balloon catheter according to claim 5, wherein the vacuum drying process comprises:

and arranging the rapamycin and/or rapamycin derivative drug particles obtained by multiple filtering in a vacuum environment, wherein the temperature of the vacuum environment ranges from 20 ℃ to 80 ℃, and the treatment time is 0.1h to 12h.

7. The method for preparing a drug-coated balloon catheter according to claim 1,

the second water bath ultrasonic treatment comprises the following steps: carrying out water bath treatment on the bottom layer mixture, wherein the temperature range of the water bath is 20-40 ℃; and meanwhile, carrying out ultrasonic treatment on the bottom layer mixture subjected to the water bath, wherein the frequency range of the ultrasonic treatment is 10-80 khz, and the treatment time is 1-20 min.

8. The method for preparing a drug-coated balloon catheter according to claim 7, wherein the primer coating process comprises:

and arranging the balloon body in the bottom layer mixed liquid subjected to the second water bath ultrasonic treatment for ultrasonic treatment, wherein the frequency range of the ultrasonic treatment is 10-80 khz, and the treatment time is 1-20 min.

9. The method for preparing a drug-coated balloon catheter according to claim 8,

the processing time of the bottom layer is 0.1 to 24 hours after being dried in dark.

10. The method for preparing a drug-coated balloon catheter according to claim 1, wherein the surface coating treatment comprises;

and arranging the balloon body subjected to bottom coating treatment in the surface layer mixed solution for soaking for 0.1-60 min.

11. The method for preparing a drug-coated balloon catheter according to claim 10,

and (3) carrying out surface layer shading drying treatment on the balloon body subjected to surface layer coating treatment, wherein the treatment time is 0.1-24 h.

12. A drug-coated balloon catheter produced by the method for producing a drug-coated balloon catheter according to any one of claims 1 to 11,

the drug balloon catheter comprises at least one bottom drug coating and at least one surface drug coating.